Gabapentin (Neurontin®) is an anti-convulsant agent that is useful in the treatment of epilepsy and that has recently been shown to be a potential treatment for neurogenic pain. It is 1-(aminomethyl)-cyclohexaneacetic acid of structural formula: 
Gabapentin is one of a series of compounds of formula in which R1 is hydrogen or a lower alkyl radical and n is 4, 5, or 6. These compounds are described U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No. 4,087,544. Their disclosed uses are: protective effect against cramp induced by thiosemicarbazide; protective action against cardiazole cramp; the cerebral diseases, epilepsy, faintness attacks, hypokinesia, and cranial traumas; and improvement in cerebral functions. The compounds are useful in geriatric patients. The disclosures of the above two patents are hereby incorporated by reference.
WO 99/21824, whose disclosure is also incorporated by reference, discloses further cyclic amino acids that are useful in the treatment of epilepsy, faintness attacks, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammation, especially arthritis. The compounds disclosed include those of the formula: and salts thereof, in which:
R is hydrogen or a lower alkyl;
R1 to R8 are each independently selected from hydrogen, straight or branched alkyl of from 1 to 6 carbons, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, hydroxymethyl, amino, aminomethyl, trifluoromethyl, —CO2H, —CO2R15, —CH2CO2H, —CH2CO2R15, —OR15 wherein R15 is a straight or branched alkyl of from 1 to 6 carbons, phenyl, or benzyl, and R1 to R8 are not simultaneously hydrogen.
The compounds of WO 99/21824 may be synthesized:                using a general strategy (General Scheme 1) outlined by G. Griffiths et al., Helv. Chim. Acta, 1991; 74:309;        analogously to the published procedure for the synthesis of 3-oxo-2,8-diazaspiro[4,5]decane-8-carboxylic acid tert-butyl ester, see P. W. Smith et al., J. Med. Chem., 1995; 38:3772 (General Scheme 2);        by the methods outlined by G. Satzinger et al., (Ger Offen 2,460,891; U.S. Pat. No. 4,024,175, and Ger Offen 2,611,690; U.S. Pat. No. 4,152,326) (General Schemes 3 and 4);        by a route outlined by G. Griffiths et al., Helv. Chim. Acta, 1991; 74:309 (General Scheme 5). (i) Ethyl cyanoacetate, piperidine (Cope et al., J. Am. Chem. Soc., 1941; 63:3452); (ii) NaCN, EtOH/H2O; (iii) EtOH, HCl; (iv) H2O/H+; (v) H2, Rh/C, MeOH; (vi) HCl. (i) Ph3P═CHCO2Me; (ii) MeNO2, 1,1,3,3-tetramethylguanidine; (iii) Raney nickel, EtOH/H2O; (iv) HCl. (i) Ethylcyanoacetate, ammonia then H3O+; (ii) H2SO4; (iii) Ac2O; (iv) MeOH; (v) Curtius Reaction; (vi) HCl, H2O then anion exchange. (i) Ethylcyanoacetate, ammonia then H3O+; (ii) H2SO4; (iii) Ac2O; (iv) H2NOH; (v) PhSO2Cl; (vi) Et3N, MeOH; (vii) HCl, H2O then anion exchange. (i) Ethyl cyanoacetate, piperidine (Cope et al., J. Am. Chem. Soc., 1941; 63:3452); (ii) NaCN, EtOH/H2O; (iii) BnOH, HCl; (iv) H2O/H+; (v) H2, Rh/C, MeOH.        
Intermediates disclosed in WO 99/21824 include the following: 
Our U.S. patent application Ser. No. 60/169602, the disclosure of which is also incorporated herein by reference, describes and claims methods for the stereocontrolled synthesis of five-member ring Gabapentin analogues that are pure stereoisomers of compounds of formulae shown below and to salts thereof. wherein R represents C1-C10 alkyl and C3-C10 cycloalkyl. The synthesis starts with the Knoevenagel condensation of a 3-substituted cyclopentanone of the kind described above with ethyl cyanoacetate and proceeds via the key intermediates 
A method for preparing a compound of formula (7) in the following reaction scheme and pharmaceutically acceptable salts thereof comprises:                a) adding ethyl cyanoacetate to a mixture of a chiral cyclopentanone of formula (1) in a solvent to which a C1-C6 carboxylic acid and an amphoteric catalyst were added, and stirring the mixture to produce the alkene of formula (2);        b) adding the product of Step a) above to a mixture of benzylmagnesium chloride in a dry solvent to produce the addition product of formula (3);        c) adding the product of Step b) above to a mixture of a base in a solvent and stirring the mixture to produce the carboxylic acid of formula (4);        d) contacting the product of Step c) above with (S)-α-methyl-benzylamine in a solvent, and recrystallizing the salt so formed to produce the enriched diastereomer of formula (5) as the (S)-α-methyl-benzylamine salt;        e) adding the product of Step d) to an inorganic acid dissolved in a solvent and stirring to produce the carboxylic acid of formula (6);        f) adding the product of Step e) to a mixture of iodomethane in a solvent to which 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added, and stirring to produce the ester of formula (7);        g) adding the product of Step f) to a mixture of carbon tetrachloride and acetonitrile to which water, sodium periodate, and ruthenium(II) chloride were added, and stirring to produce the carboxylic acid of formula (8);        h) adding the product of Step g) to a mixture of an amine base and a solvent to which diphenylphosphoryl azide (DPPA) was added, and stirring to produce the isocyanate of formula (9);        i) adding the product of Step h) to a solvent to which methanol was added, and stirring to produce the carbamate of formula (10);        j) adding the product of Step i) to a solvent to which aqueous hydrochloric acid was added, and stirring to produce a compound of Formula Ia;        k) converting the product of Step j) to a compound of Formula I, and further converting, if desired, to a pharmaceutically acceptable salt by known means:         
Preparation of a compound of formula II can proceed by a method which involves following the above-described sequence of steps (a) to (e) to produce the intermediate of step (6), and thereafter following the further steps indicated below:                f) adding the product of Step e) to a mixture of an amine base and a solvent to which diphenylphosphoryl azide (DPPA) was added, and stirring to produce the isocyanate of formula (11);        g) adding the product of Step f) to a solvent to which methanol was added and stirring to produce the carbamate of formula (12);        h) adding the product of Step g) to a mixture of carbon tetrachloride and acetonitrile to which water, sodium periodate, and ruthenium(III) chloride were added, and stirring to produce the carboxylic acid of formula (13);        i) adding the product of Step h) to a solvent to which aqueous hydrochloric acid was added, and stirring to produce a compound of Formula IIa;        k) converting the product of Step i) to a compound of Formula II, and further converting, if desired, to a pharmaceutically acceptable salt by known means:         
An alternative route to the compounds of formula (II), also proceeding from compound (6) above involves the further steps of:                f) adding oxalyl chloride to a mixture of the product of Step e) and a solvent to which N,N-dimethylformamide (DMF) was added, and stirring to produce the acid chloride of formula (14);        g) adding the product of Step f) to a mixture of tert-butyl alcohol in a solvent to which an amine base was added, and stirring to produce the ester of formula (15);        h) adding the product of Step g) to a mixture of carbon tetrachloride and acetonitrile to which water, sodium periodate, and ruthenium(III) chloride were added, and stirring to produce the carboxylic acid of formula (16);        i) adding the product of Step h) to a solvent to which methanol and (trimethylsilyl)diazomethane were added, and stirring to produce the bis ester of formula (17);        j) adding an acid to a mixture of the product from Step i) and a solvent and stirring to produce the carboxylic acid of formula (18);        k) adding the product of Step j) to a mixture of an amine base and a solvent to which diphenylphosphoryl azide (DPPA) was added, and stirring to produce the isocyanate of formula (19);        l) adding the product of Step k) to a solvent to which methanol was added and stirring to produce the carbamate of formula (20);        m) adding the product of Step 1) to a solvent to which aqueous hydrochloric acid was added, and stirring to produce a compound of Formula IIa;        n) converting the product of Step m) to a compound of Formula II, and further converting, if desired, to a pharmaceutically acceptable salt by known means:         
Compounds of formula (III) can be prepared by processes that involve the same steps as those for the compounds of formula (I), for example by following the sequence of reactions set out below: 
Similarly, compounds of formula (IV) may be made by a sequence of reactions analogous to those described above: 
It will be noted that the synthetic methods disclosed in both WO 99/21824 and U.S. Ser. No. 60/169,602 rely on 3- or 3,4-substituted cyclopentanones.